Modified saccharides, conjugates thereof, and their manufacture

Abstract

Saccharide-protein conjugates having a new type of linker are described. The conjugates comprising the new linker are prepared from modified saccharides comprising a moiety of the formula (I): -A-N(R 1 )-L-M wherein: A is a bond, —C(O)— or —OC(O)—; R 1 is selected from H or C 1 -C 6 alkyl; L is a C 1 -C 12 alkylene group; and M is a masked aldehyde group. The new linker is especially useful for preparing conjugates of Neisseria meningitidis serogroup A saccharide. Conjugates having this new linker have improved immunogenicity compared to other types of conjugates.

1 . A modified capsular saccharide comprising a moiety of the formula (I):
   -A-N(R 1 )-L-M  (I)
   
       wherein:
 A is a bond, —C(O)— or —OC(O)— 
 R 1  is selected from H or C 1 -C 6  alkyl; 
 L is a C 1 -C 12  alkylene group; 
 M is a masked aldehyde group. 
 
     
     
         2 . The modified capsular saccharide of  claim 1  wherein A is —OC(O)—. 
     
     
         3 . The modified capsular saccharide of  claim 1  wherein R 1  is H. 
     
     
         4 . The modified capsular saccharide of  claim 1  wherein L is a C 1 -C 6  alkylene group. 
     
     
         5 . The modified capsular saccharide of  claim 4  wherein L is —CH 2 CH 2 CH 2 —. 
     
     
         6 . The modified capsular saccharide of  claim 1  wherein the masked aldehyde is selected from: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2  is selected from H, C 1 -C 12  alkyl, C 3 -C 12  cycloalkyl, C 5 -C 12  aryl or C 5-12  aryl-C 1-6  alkyl; 
 X and Y are the same or different and are independently selected from O or S; 
 R 3  and R 4  are independently selected from C 1 -C 12  alkyl, C 3 -C 12  cycloalkyl, C 5 -C 12  aryl or C 5-12  aryl-C 1-6  alkyl; or R 3  and R 4  are joined to form a C 3 , C 4 , C 5 , C 6 , C 7  or C 8  cycloalkyl ring containing the heteroatoms X and Y; 
 R 5  and R 6  are independently selected from H, C 1 -C 12  alkyl, C 3 -C 12  cycloalkyl, C 5 -C 12  aryl or C 5-12  aryl-C 1-6  alkyl; or R 5  and R 6  are joined to form a C 3  or C 12  cycloalkyl ring; 
 R 9  and R 10  are independently selected from H, C 1 -C 12  alkyl, C 3 -C 12  cycloalkyl, C 5 -C 12  aryl or C 5-12  aryl-C 1-6  alkyl; or R 9  and R 10  are joined to form a C 3  to C 12  cycloalkyl ring; and 
 R 7  and R 8  are independently selected from C 1 -C 12  alkyl or C 3 -C 12  cycloalkyl groups. 
 
     
     
         7 . The modified capsular saccharide of  claim 6  wherein the masked aldehyde is
   —CH(OH)CH 2 OH.
 
 
     
     
         8 . The modified capsular saccharide of  claim 1  comprising a moiety of the formula: —NH(CH 2 ) 3 CH(OH)CH 2 OH. 
     
     
         9 . The modified saccharide of  claim 1  comprising a moiety of the formula:
   —OC(O)NH(CH 2 ) 3 CH(OH)CH 2 OH.
 
 
     
     
         10 . A modified capsular saccharide comprising a moiety of the formula (II):
   -A-N(R 1 )-L-C(O)H  (II)
   wherein A, R 1  and L are as defined in  claim 1 .   
     
     
         11 . The modified capsular saccharide of  claim 10  wherein A is —OC(O)—. 
     
     
         12 . The modified capsular saccharide of  claim 10  comprising a moiety of the formula: —NH(CH 2 ) 3 C(O)H. 
     
     
         13 . The modified capsular saccharide of  claim 10  comprising a moiety of the formula: —OC(O)NH(CH 2 ) 3 C(O)H 
     
     
         14 . The modified capsular saccharide of  claim 1  wherein the capsular saccharide is  Neisseria meningitidis  serogroup A saccharide. 
     
     
         15 - 45 . (canceled)